Projects for the current call are listed below. The application form will ask for one project to be selected or two projects to be ranked in order of preference.
Designing delivery platforms for nucleic acid vaccines using supramolecular chemistry / John Tregoning
Designing delivery platforms for nucleic acid vaccines using supramolecular chemistry
The ongoing COVID-19 pandemic has shown that advanced vaccines are needed urgently to tackle global health challenges. The ability to deliver genes directly to cells has transformed the vaccine landscape. Nucleic acid vaccines have enormous potential, but safe and efficient introduction of active genetic material into cells for effective expression can be complex and challenging. Improving gene delivery is a priority to realise the potential of nucleic acid therapeutics.
The aim of this project is to optimise gene delivery. It is a collaboration that draws upon the formulation expertise of Aqdot and the vaccine expertise of the Tregoning/ Shattock groups at Imperial College, London. We will exploit supramolecular chemistry to develop new delivery platforms, based on a novel “host” molecule (cucurbituril, CB). Early data suggest this elegant and conceptually simple supramolecular-polyplex approach will be successful, safe, low-cost, scalable and flexible to a wide range of applications. Aqdot, the partner company, was spun out of Cambridge University in 2013 and has developed this proprietary delivery technology. The student will undertake in vitro and in vivo studies at Imperial College focusing on nasal delivery of gene-based vaccines directly to the lungs.
During placements at Aqdot, the student’s studies will focus on formulation design, characterisation and stability of supramolecular polyplexes. The student will therefore learn a range of skills including immunology and formulation, in the context of a dynamic biotech start-up.
Developing advanced mass photometry methods for analysis of the multi-step helicase loading process / Christian Speck
Developing advanced mass photometry methods for analysis of the multi-step helicase loading process
The student will use and develop a novel single-molecule biophysical method (mass-photometry) to investigate a key step in DNA replication, the loading of the replicative helicase on DNA, and explore this multi-step reaction in a time resolved manner. This work will address how DNA replication works and contribute to the development of helicase loading inhibitors as a potential anti-cancer therapy.
The project is a collaboration between Refeyn Ltd and the Imperial College London research groups of Professor Speck and Professor Rueda. Refeyn, a company based in Oxford, has recently developed and brought to market a breakthrough technology that measures the molecular weight of individual proteins and protein complexes by mass photometry. This revolutionary biophysical technique is highly-accurate, very fast, label-free and allows the use of native proteins.
The PhD student will apply this technology to investigate a multi-step reaction in a time resolved manner and will also optimize the detector surface for kinetic analysis. During the course of work, the student will identify assembly intermediates in the multi-step helicase loading pathway to reveal how the process works at a molecular level and how it can be inhibited in cancer cells. As part of a 3-month internship with Refeyn, the student will gain unprecedented insights into mass photometry, benefit from access to expert knowledge and non-released software, develop expertise in data analysis and surface chemistries and gain insights into a rapidly growing biotechnology company that specialises on innovative analytic approaches.
The Speck and Rueda labs employ biophysical, biochemical, structural (cryo-EM) and single-molecule research in order to investigate the genome editing CRISPR/Cas enzyme, the replication machinery, sister chromatid cohesion and the chromatin structure. By forming new group-internal collaborations, the student will be able to apply mass-spectrometry in a number of settings and get insights into several research projects. The research groups provide a vibrant and supportive atmosphere that is ideal for the development of this cutting-edge biophysical research project.
The ideal candidate has a 2.1 degree or better, background in biophysics, biochemistry and/or chemistry, enjoys to work with proteins and is interested in data analysis and method development. Experience/interest in computer programming e.g. python would be an advantage.
Enabling rapid and portable detection of bacterial infections on a silicon bio-chip / Pantelis Georgiou
Enabling rapid and portable detection of bacterial infections on a silicon bio-chip
Bacterial infections are becoming increasingly resistant to antibiotics, giving rise to new 'superbugs' which cannot be killed by our usual treatment strategies, leading to 25,000 deaths in the EU each year and a healthcare cost of over €1.5 billion annually. Bacterial resistance is also predominant for viral infections such as COVID-19 as a large proportion of patients die from a resistant secondary bacterial infection. Rapid and accessible diagnostics is the key to enabling rapid treatment and address this global threat.
The objective of this project is to develop new methods for a scalable and low-cost test to rapidly distinguish bacterial and viral infections by detecting proteins or antibodies released by the body as a response to the disease. The test will be implemented using a small bio-chip in silicon technology, the same cutting-edge technology as smartphones and computers. This project will be led as a collaboration between Dr Georgiou who has innovated novel bio-chips, Prof Levin who has pioneered host response diagnostics and Mologic who has developed world-leading techniques for rapid and cheap paper-based tests.
The student will discover new markers based on high-quality patient databases (Y1), develop a novel immunoassay for the markers in collaboration with Mologic (Y1), translate the assay to the bio-chip (Y2), develop new algorithms for diagnosis (Y3) and validate with bio-banked samples (Y3). These outcomes will contribute to the development of a rapid, low-cost and scalable test plugged to a smartphone, ideally suited for future deployment in the UK and low- and middle-income countries.
Evaluation of mechanisms of action and utility of a new prostate cancer therapeutic, CT7001 / Charlotte Bevan
Evaluation of mechanisms of action and utility of a new prostate cancer therapeutic, CT7001
Prostate cancer, like many other tumour types, is “addicted” to transcription - prostate cancer cells require increased levels of transcription to grow. Uniquely it is also addicted to androgens (male steroid hormones), which signal via the androgen receptor. Both these addictions provide a therapeutic opportunity, which we propose to exploit simultaneously by inhibiting cyclin-dependent kinase 7 (CDK7). CDK7 is important both for transcription and androgen receptor activity, and a new CDK7 inhibitor drug, developed at Imperial and in clinical trials for prostate cancer in partnership with Carrick Therapeutics, can block androgen signalling and prostate tumour growth, in vitro and in vivo
We will determine precisely how CDK7 inhibition by our drug inhibits androgen receptor activity via its interaction with a critical cofactor protein recently shown to be important in prostate cancer progression. We will assess downstream effects on gene expression and cancer-associated processes. We will test whether CDK7 inhibition improves performance of already-established prostate cancer drugs when in combination, to prolong life expectancy and improve quality-of-life for men with advanced, therapy-resistant prostate cancer. Importantly, we may also identify markers to select which men would benefit from this treatment.
The student will be embedded in a highly active and collaborative research group and trained in a wide range of established and state-of-the-art molecular biology techniques, plus analysis of large datasets and, optionally, in vivo techniques. They will benefit from liaison with the prostate surgical team and partners at Carrick, who will provide further training in drug selection, biomarker selection and assay development.
Genomic characterisation of gestational trophoblastic tumours and associated circulating tumour DNA to improve patient ... / Michael Seckl
Genomic characterisation of gestational trophoblastic tumours and associated circulating tumour DNA to improve patient management and diagnosis
Gestational trophoblastic neoplasms (GTN) are a group of pregnancy-related cancers that develop from cells which normally form the placenta. Whilst the majority of patients are cured with chemotherapy, unfortunately some, with rarer subtypes, still succumb to their disease. Therefore, it is imperative that we understand the molecular mechanisms underpinning these rarer tumours in order to improve patient management and outcomes. To do so, we will analyse the DNA of GTN samples to identify errors (“mutations”) that may help us to determine why the tumours develop and why some do not respond to treatment. Whilst diagnosis is typically dependent on tumour tissue taken via invasive biopsies or surgery, these can induce life-threatening haemorrhage because of the tumours’ highly vascular nature.
Fortunately, we have shown that DNA from GTN tumours can be detected in patients’ blood thereby avoiding the need for biopsies. We aim to utilise this ‘circulating tumour DNA’ (ctDNA) to develop a non-invasive test to diagnose GTN and use it as a novel means to investigate the tumours, including monitoring throughout the course of a patient’s treatment. This genomics project provides a multidisciplinary platform for the student to become accomplished in cutting-edge wet-lab and bioinformatics/data analysis skills, supported by Nonacus Ltd, a company that has extensive expertise in the technical and analytical approaches required. The data obtained here will lead to direct improvements in clinical diagnosis and patient management and may result in the identification of new therapeutics.
Novel contrast enhanced ultrasound imaging approaches to understand and treat gastrointestinal disease / Kevin Murphy
Novel contrast enhanced ultrasound imaging approaches to understand and treat gastrointestinal disease
Diseases of the gastrointestinal tract are global public health problems. Understanding how disease effects the gut, and how blood flow to the gut is altered by disease can offer new insights into potential therapies. This project will use ground-breaking contrast enhanced ultrasound (CEUS) imaging approaches in animal models to investigate how the gut works and how gut function alters in gut diseases such as inflammatory bowel disease.
Based on our exciting pilot data, the student will further refine the CEUS methodology, increasing its ability to detect tiny regional changes in blood flow in the rodent gut without the need for surgery, and using it to investigate what happens to blood flow in the small blood vessels of the rodent gut in response to physiological challenges. They will then validate its use in rodent models of gut disease, mapping blood flow to processes including gut growth, turnover and inflammation . New potential therapies designed by our industrial partner Sosei Heptares will then be tested for their ability to treat gut disease in these models. Finally, the student will investigate the wider utility of this approach to other disease models.
The student on this project will learn interdisciplinary skills including engineering expertise in ultrasound, mathematical modelling of data, and the use of animal models. They will have the chance to carry out world leading research and the opportunity to work with a company taking an exciting and novel approach to drug design in this therapeutic area. Students will be expected to be involved in the design and conduct of experiments, and to publish and present their work at national and international conferences. Students will complete the necessary home office training to receive a personal licence and will be trained in in vitro and in vivo techniques. The Section hosts a seminar series from eminent speakers and there is a weekly journal club to train students how to critically approach the scientific literature. They will also complete a series of courses from the award-winning Imperial College Graduate School. There will be opportunities to be given training in teaching, and to teach undergraduate students and to get involved in Outreach activities for school pupils.
Successful applicants will be joining an internationally-renowned research group, within one of the world’s top research universities. The research group is welcoming and friendly; students are well supported and have gone on to careers in academia, industry and beyond.
Using systems pharmacology to unravel the influence of nutrient supply and TP53 loss on MAT2A inhibitor efficacy and toxicity / Hector Keun
Using systems pharmacology to unravel the influence of nutrient supply and TP53 loss on MAT2A inhibitor efficacy and toxicity
A key concept in modern cancer therapy is to exploit the fact that some parts of the genome are lost in cancer cells but not healthy cells, making them uniquely reliant on other genes which can be targeted by drugs (synthetically lethal genes). Recently it was discovered that inhibiting the metabolic enzyme MAT2A can selectively kill tumour cells which have lost a part of a chromosome containing another related enzyme MTAP. This strategy offers huge promise to treat some highly lethal cancers. But because such drugs interfere with metabolism we do not know how the benefits of the drug could change depending on the nutrients available to the cell, nor the potential long-term side effects the drug might cause in organs which are very active in human metabolism, such as in the liver.
This project aims to answer those questions so that we can target MAT2A inhibitors more accurately and safely to the patients that are most likely to benefit from this exciting new therapy. The student will get world-class training in many aspects of drug discovery, validation of drug targets, drug safety assessment, use of different cell and organ models, genetic engineering of cell models, metabolic analysis and metabolic tracking studies, computational ‘big data’ analysis including analysis of RNA sequencing data. The training will be conducted by expert groups at Imperial together with one of the world’s biggest pharmaceutical companies, AstraZeneca.